Hyponatremia is an important electrolyte abnormality with a potential for significant morbidity and mortality. It is a condition of a positive balance of water with or without a deficit of sodium, which is recognized when the plasma sodium falls below the level of 135 mmol/L. Hyponatremia is a condition that can occur in isolation in individuals that over-consume water; however, more often hyponatremia is a complication of medication or other underlying medical conditions that lead to a diminished excretion of water.
Hyponatremia may lead to water intoxication, which occurs when the normal tonicity of extracellular fluid falls below the safe limit, due to retention of excess water. Water intoxication is a potentially fatal disturbance in brain function. Typical symptoms of water intoxication include nausea, vomiting, headache, and malaise. Since nausea is also a stimulus for the release of anti-diuretic hormone (ADH), which causes water retention, a positive feedback loop may occur that can further worsen the symptoms of hyponatremia. As the hyponatremia condition worsens, the patient may experience reduced reflexes, convulsions, stupor, coma, or even death.
Most cases of hyponatremia are associated with reduced plasma osmolarity and often occur as a result of water retention in the body. The majority of adult cases are related to increased release or activity of ADH, also known as vasopressin, arginine vasopressin, or argipressin. In normal physiology, a low plasma volume may trigger the release of ADH. ADH causes water retention by the kidney and a decrease in urine volume. As a result, the kidney produces concentrated urine and the plasma volume is increased. Reduction and restoration of plasma volume stops the ongoing release of ADH and water retention; consequently, plasma sodium levels return to the normal range. However, rapid correction of plasma volume and sodium concentration must be avoided to reduce the risk of central pontine myelinolysis especially in patients with chronic hyponatremia.
Some patients with hyponatremia have normal levels of plasma volume. In those patients, other physiological signals might have triggered ADH release and subsequent water retention. In other cases, the patient may have Syndrome of Inappropriate ADH (SIADH). SIADH represents the sustained, non-physiologic release of ADH, and most often occurs as a side effect of certain medicines or complications of other diseases.
Another class of patients with hyponatremia is said to be hypervolemic. Patients with this type of hyponatremia have expanded extracellular fluid volume, but “underfilling,” i.e., reduced “effective” blood volume, of the arterial circulation. Since underfilling of the arterial circulation is a potent stimulus for ADH release, this type of patient often retains water and becomes hyponatremic. Treatment of these patients involves treating the underlying diseases that had caused the arterial underfilling. However, this is often difficult to do, since the common underlying diseases (such as liver cirrhosis and heart failure) are notoriously difficult to treat.
Treating hyponatremia thus remains a clinical challenge. Patients with acute and severe hyponatremia need urgent treatment to quickly draw water out of the skull to prevent the development of brain herniation. Treatment of chronic hyponatremia, however, faces additional challenges. An effective treatment must avoid a rapid rise in plasma sodium concentration, which is usually the result of a rapid decrease in ADH activity in the kidney. Most often, this occurs following the intake of sodium chloride in patients who had a large deficit of sodium: correction of sodium deficit in the body by sodium intake results in a decrease in ADH concentration in the kidney, and a rapid excretion of water. Thus, once the rapid excretion of water and an overly rapid rise in plasma sodium concentration are recognized, a long acting form of ADH, such as dDAVP (Desmopressin) should be given promptly to stop water diuresis immediately.
Correcting the positive balance of water by merely restricting the intake of water is rarely a sufficient therapy for the patient with chronic hyponatremia. Thus, the treatment often also includes the administration of ADH antagonists; this treatment is, however, not without risks. In more detail, these ADH antagonists may cause a rapid increase in the excretion of water in the urine, which may result in an abrupt rise in the sodium concentration in plasma, which may result in osmotic demyelination, permanent neurological disorders, and possibly death. Therefore, it is clear that better and safer treatment for patients with hyponatremia, particularly chronic hyponatremia is needed, especially in those patients who are at greater risk for developing osmotic demyelination—i.e., those with a deficiency of potassium, and those who are malnourished.